Rasagiline formulations and processes for their preparation

ABSTRACT

The subject invention provides a pharmaceutical composition comprising N-propargyl-1(R)-aminoindan mesylate; a pharmaceutically acceptable carrier; and greater than 0.7 ppm but less than 30 ppm in total of a compound having the structure: 
                         
and any salts of the compound.

This application is a divisional of U.S. Ser. No. 11/634,916, filed Dec.5, 2006, which claims benefit of U.S. Provisional Application No.60/742,823, filed Dec. 6, 2005, the contents of all of which are herebyincorporated by reference.

Throughout this application various publications, published patentapplications, and patents are referenced. The disclosures of thesedocuments in their entireties are hereby incorporated by reference intothis application in order to more fully describe the state of the art towhich this invention pertains.

BACKGROUND OF THE INVENTION

Rasagiline is a selective irreversible inhibitor of monoamine oxidaseenzyme Type-B (MAO-B) and has the chemical nameN-propargyl-1(R)-aminoindan (“(R) —PAI”). Its structural formula is:

(R)-PAI is an active MAO-B inhibitor while the correspondingS-enantiomer (“(S)-PAI”) shows extremely low MAO-B inhibitory activity(U.S. Pat. No. 6,316,504). It has also been found that (R)-PAI has adegree of selectivity for MAO-B inhibition surprisingly higher than thatof the corresponding racemic form (U.S. Pat. No. 6,316,504). The factthat (R)-PAI is more active than the racemic mixture for the inhibitionof MAO-B is a reflection of the extremely low activity of (S)-PAI forinhibition of MAO-B (U.S. Pat. No. 6,316,504).

Rasagiline, its salts, preparation and use for the treatment ofParkinson's disease, Alzheimer's Disease, memory disorders, stroke andother disorders have been the subject of numerous patents, includingU.S. Pat. Nos. 5,387,612, 5,453,446, 5,457,133, 5,668,181, 5,576,353,5,532,415, 5,599,991, 5,786,390, 5,519,061, 5,891,923, 5,744,500 and6,316,504, the contents of which are hereby incorporated by reference.Rasagiline formulations are described in U.S. Pat. No. 6,126,968, thecontents of which are also hereby incorporated by reference.

SUMMARY OF THE INVENTION

The subject invention provides a pharmaceutical composition comprisingN-propargyl-1(R)-aminoindan mesylate; a pharmaceutically acceptablecarrier; and greater than 0.7 ppm but less than 30 ppm in total of acompound having the structure:

and any salts of the compound.

The subject invention also provides a process for preparing apharmaceutical product comprising N-propargyl-1(R)-aminoindan mesylateand a pharmaceutically acceptable carrier, wherein the pharmaceuticalproduct has less than 30 ppm in total ofN-2-propene-1-yl-2-chloro-(R)-aminoindan and any salts thereof, theprocess comprising

-   -   a) obtaining a batch of N-propargyl-1(R)-aminoindan mesylate;    -   b) determining the total amount of        N-2-propene-1-yl-2-chloro-(R)-aminoindan and any salts thereof        present in the batch; and    -   c) preparing the pharmaceutical product from the batch only if        the batch is determined to have less than 30 ppm in total of        N-2-propene-1-yl-2-chloro-(R)-aminoindan and salts thereof.

The subject invention also provides a process for validating a batch ofa pharmaceutical product containing N-propargyl-1(R)-aminoindan mesylateand at least one pharmaceutically acceptable carrier for distributioncomprising

-   -   a) subjecting a sample of the batch to stability testing;    -   b) determining the total amount of        N-2-propene-1-yl-2-chloro-(R)-aminoindan and any salts thereof        in the sample of the batch after stability testing; and    -   c) validating the batch for distribution only if the sample of        the batch after stability testing contains less than 30 ppm in        total of N-2-propene-1-yl-2-chloro-(R)-aminoindan and salts        thereof.

The subject invention also provides a process of making a pharmaceuticalcomposition comprising N-propargyl-1(R)-aminoindan mesylate and at leastone pharmaceutically acceptable carrier, the process comprising admixingthe N-propargyl-1(R)-aminoindan mesylate with the at least onepharmaceutically acceptable carrier, wherein the at least onepharmaceutically acceptable carrier is free of a chloride-containingcompound.

The subject invention also provides a process for testing whether asample contains an undesirable chlorinated N-allyl aminoindan whichcomprises determining whether the sample contains a compound having thestructure:

wherein one of R₁, R₂ or R₃ is Cl and the remainder are H, or a saltthereof.

The subject invention also provides an isolated compound having thestructure:

wherein one of R₁, R₂ or R₃ is Cl and the remainder are H, or a saltthereof, wherein the isolated compound is free of anN-propargyl-1-aminoindan or a salt thereof.

The subject invention also provides a compound having the structure:

wherein one or more of the carbons is ¹³C, one of R₁, R₂ or R₃ is Cl andthe remainder are H, or a salt thereof.

The subject invention also provides a composition comprising a compoundhaving the structure:

wherein one of R₁, R₂ or R₃ is Cl and the remainder are H, or a saltthereof; and a carrier, wherein the composition is free of anN-propargyl-1-aminoindan or a salt thereof.

The subject invention also provides a process of manufacturingN-2-propene-1-yl-3-chloro-cis-aminoindan,N-2-propene-1-yl-3-chloro-trans-aminoindan, or an enantiomer or a saltof any one thereof, comprising reacting a compound having the structure:

with 1,3-dichloropropene in the presence of a base andN,N-dimethylacetamide so as to produce the compound.

The subject invention also provides a process of manufacturing(1,2,3)¹³C—N-2-propene-1-yl-2-chloro-aminoindan or an enantiomer or asalt thereof, comprising:

-   -   a) heating a mixture of (1,2,3)¹³C-aminoindan and a base in a        first suitable solvent,    -   b) adding 2,3-dichloro-1-propene to produce        (1,2,3)¹³C—N-propargyl-1-aminoindan,    -   c) reacting the (1,2,3)¹³C—N-propargyl-1-aminoindan of step b)        with HCl in the presence of a second suitable solvent to produce        the compound.

The subject invention also provides use ofN-2-propene-1-yl-2-chloro-aminoindan, (1,2,3)¹³C—N-2-propene-1-yl-2-chloro-aminoindan,N-2-propene-1-yl-3-chloro-cis-aminoindan,N-2-propene-1-yl-3-chloro-trans-aminoindan, or an enantiomer or a saltof any one thereof, as a reference standard to detect trace amounts ofimpurities in a pharmaceutical composition.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 ¹H nuclear magnetic resonance (NMR) spectrum of a sample ofN-2-propene-1-yl-2-chloroaminoindan hydrochloride obtained on a Bruker200 MHz apparatus in DMSO-d₆.

FIG. 2 Infrared spectrum (IR) of a sample ofN-2-propene-1-yl-2-chloroaminoindan hydrochloride in KBr, measured witha Nicolet Avatar 320 FT-IR apparatus. The IR spectrum of a KBr pellet ata concentration of about 2% exhibits a typical absorption band at 1579cm⁻¹ (Cl-substituted alkenyl group).

FIG. 3 Scheme 1—preparation of trans-3-Chloro-AAI and cis-3-Chloro-AAI.

FIG. 4 Scheme 2—preparation of 2-Chloro-AAI and cis-3-Chloro-AAI.

FIG. 5 Scheme 3—preparation of 2-Chloro-AAI MES, trans-3-Chloro-AAI MESand cis-3-Chloro-AAI MES.

DETAILED DESCRIPTION

The subject invention provides a pharmaceutical composition comprisingN-propargyl-1(R)-aminoindan mesylate; a pharmaceutically acceptablecarrier; and greater than 0.7 ppm but less than 30 ppm in total of acompound having the structure:

and any salts of the compound.

By greater than 0.7 ppm but less than 30 ppm it is meant that all tenthand integer unit amounts within the range are specifically disclosed aspart of the invention. Thus, 0.7, 0.8, 0.9 and 1, 2, 3, 4, . . . 27, 28,29 and 30 ppm unit amounts are included as embodiments of thisinvention.

In one embodiment, the pharmaceutical composition comprises greater than1 ppm, greater than 2 ppm, greater than 3 ppm, greater than 4 ppm,greater than 5 ppm, greater than 6 ppm, or greater than 7 ppm in totalof the compound and the salt of the compound.

In another embodiment, the pharmaceutically acceptable carrier does notinclude magnesium stearate.

In yet another embodiment, the pharmaceutically acceptable carriercomprises mannitol, starch, pregelatinized starch, colloidal silicondioxide, stearic acid and/or talc.

In yet another embodiment, the pharmaceutical composition is free ofmaltodextrin, croscarmellose sodium, citric acid, lactose, glycerylbehenate and hydrogenated vegetable oil type I.

The subject invention also provides a process for preparing apharmaceutical composition comprising N-propargyl-1(R)-aminoindanmesylate and a pharmaceutically acceptable carrier, wherein thepharmaceutical product has less than 30 ppm in total ofN-2-propene-1-yl-2-chloro-(R)-aminoindan and any salts thereof, theprocess comprising

-   -   a) obtaining a batch of N-propargyl-1(R)-aminoindan mesylate;    -   b) determining the total amount of        N-2-propene-1-yl-2-chloro-(R)-aminoindan and any salts thereof        present in the batch; and    -   c) preparing the pharmaceutical product from the batch only if        the batch is determined to have less than 30 ppm in total of        N-2-propene-1-yl-2-chloro-(R)-aminoindan and salts thereof.

In an embodiment of the process, the pharmaceutical composition isprepared from the batch if it contains a total amount of greater than 1ppm, greater than 2 ppm, greater than 3 ppm, greater than 4 ppm, greaterthan 5 ppm, greater than 6 ppm, or greater than 7 ppm ofN-2-propene-1-yl-2-chloro-(R)-aminoindan and salts thereof.

In another embodiment of the process, the pharmaceutical composition isprepared from the batch only if it contains a total amount of less than7 ppm, less than 6 ppm, less than 5 ppm, less than 4 ppm, less than 3ppm, less than 2 ppm, or less than 1 ppm ofN-2-propene-1-yl-2-chloro-(R)-aminoindan and salts thereof.

In yet another embodiment of the process, the step of determining, theamount is determined using a measurement of mass, ultravioletabsorption, refractive index, ionization or voltammogram.

The subject invention also provides a process for validating a batch ofa pharmaceutical product containing N-propargyl-1(R)-aminoindan mesylateand at least one pharmaceutically acceptable carrier for distributioncomprising

-   -   a) subjecting a sample of the batch to stability testing;    -   b) determining the total amount of        N-2-propene-1-yl-2-chloro-(R)-aminoindan and any salts thereof        in the sample of the batch after stability testing; and    -   c) validating the batch for distribution only if the sample of        the batch after stability testing contains less than 30 ppm in        total of N-2-propene-1-yl-2-chloro-(R)-aminoindan and salts        thereof.

In an embodiment of the process, the batch is validated if the sample ofthe batch after stability testing contains a total amount greater than0.7 ppm, greater than 1 ppm, greater than 2 ppm, greater than 3 ppm, orgreater than 4 ppm of N-2-propene-1-yl-2-chloro-(R)-aminoindan and saltsthereof.

In another embodiment of the process, the batch is validated only if thesample of the batch after stability testing contains a total amount lessthan 4 ppm, less than 3 ppm, less than 2 ppm, less than 1 ppm, or lessthan 0.7 ppm of N-2-propene-1-yl-2-chloro-(R)-aminoindan and saltsthereof.

In yet another embodiment, in the step of determining, the amount isdetermined using a measurement of mass, ultraviolet absorption,refractive index, ionization or voltammogram.

The subject invention also provides a process of making a pharmaceuticalcomposition comprising N-propargyl-1(R)-aminoindan mesylate and at leastone pharmaceutically acceptable carrier, the process comprising admixingthe N-propargyl-1(R)-aminoindan mesylate with the at least onepharmaceutically acceptable carrier, wherein the at least onepharmaceutically acceptable carrier is free of a chloride-containingcompound.

In an embodiment of the process, the at least one pharmaceuticallyacceptable carrier does not include magnesium stearate.

In another embodiment of the process, the pharmaceutical acceptablecarrier comprises mannitol, starch, pregelatinized starch, colloidalsilicon dioxide, stearic acid and/or talc.

In yet another embodiment of the process, the pharmaceutical compositionis free of maltodextrin, croscarmellose sodium, citric acid, lactose,glyceryl behenate and hydrogenated vegetable oil type I.

The subject invention also provides a process for testing whether asample contains an undesirable chlorinated N-allyl aminoindan whichcomprises determining whether the sample contains a compound having thestructure:

wherein one of R₁, R₂ or R₃ is Cl and the remainder are H, or a saltthereof. Specifically, the subject invention provides a process fortesting whether a sample contains any of specific structures describedherein.

The subject invention also provides an isolated compound having thestructure:

wherein one of R₁, R₂ or R₃ is Cl and the remainder are H, or a saltthereof, wherein the isolated compound is free of anN-propargyl-1-aminoindan or a salt thereof.

In an embodiment, the compound has the structure:

In another embodiment, the compound has the structure:

In another embodiment, the compound has the structure:

In another embodiment, the compound has the structure:

In another embodiment, the compound has the structure:

In another embodiment, the compound has the structure:

In another embodiment, the compound has the structure:

In another embodiment, the compound has the structure:

In another embodiment, the compound has the structure:

In another embodiment, the compound has the structure:

In another embodiment, the compound has the structure:

In a further embodiment of the compound, one or more of the carbons is¹³C.

In yet a further embodiment of the compound, the ¹³C is at positions 1,2 and 3.

The subject invention also provides a compound having the structure:

wherein one or more of the carbons is ¹³C, one of R₁, R₂ or R₃ is Cl andthe remainder are H, or a salt thereof.

In an embodiment of the compound, the ¹³C is at positions 1, 2 and 3.

In another embodiment, the compound has the structure:

In another embodiment, the compound has the structure:

In another embodiment, the compound has the structure:

In another embodiment, the compound has the structure:

wherein one of R₁, R₂ or R₃ is Cl and the remainder are H, or a saltthereof; and a carrier, wherein the composition is free of anN-propargyl-1-aminoindan or a salt thereof.

The subject invention also provides a process of manufacturingN-2-propene-1-yl-3-chloro-cis-aminoindan,N-2-propene-1-yl-3-chloro-trans-aminoindan, or an enantiomer or a saltof any one thereof, comprising reacting a compound having the structure:

with 1,3-dichloropropene in the presence of a base andN,N-dimethylacetamide so as to produce the compound.

In an embodiment of the process, the base is K₂CO₃.

The subject invention also provides a process of manufacturingN-2-propene-1-yl-2-chloro-aminoindan,(1,2,3)¹³C—N-2-propene-1-yl-2-chloro-aminoindan,N-2-propene-1-yl-3-chloro-cis-aminoindan, or an enantiomer or a salt ofany one thereof, comprising reacting N-propargyl-1-aminoindan withhydrochloric acid in the presence of a suitable solvent so as to producethe compound.

In an embodiment of the process, the solvent is a mixture of toluene andwater.

The subject invention also provides a process of manufacturing(1,2,3)¹³C—N-2-propene-1-yl-2-chloro-aminoindan or an enantiomer or asalt thereof, comprising:

-   -   a) heating a mixture of (1,2,3)¹³C-aminoindan and a base in a        first suitable solvent,    -   b) adding 2,3-dichloro-1-propene to produce (1,2,3)        ¹³C—N-propargyl-1-aminoindan,    -   c) reacting the (1,2,3)¹³C—N-propargyl-1-aminoindan of step b)        with HCl in the presence of a second suitable solvent to produce        the compound.

In an embodiment of the process, the base is K₂CO₃.

In another embodiment of the process, the first suitable solvent isacetonitrile.

In another embodiment of the process, the second suitable solvent isether.

In yet another embodiment, the process further comprises recovering thecompound so produced.

The subject invention also provides use ofN-2-propene-1-yl-2-chloro-aminoindan,(1,2,3)¹³C—N-2-propene-1-yl-2-chloro-aminoindan,N-2-propene-1-yl-3-chloro-cis-aminoindan,N-2-propene-1-yl-3-chloro-trans-aminoindan, or an enantiomer or a saltof any one thereof, as a reference standard to detect trace amounts ofimpurities in a pharmaceutical composition.

In one embodiment, the impurity is a by-product. In another embodiment,the impurity is a degradant.

The (R) enantiomer forms of the compounds of the invention are referredto, for example, as follows: N-2-propene-1-yl-2-chloro-(R)-aminoindan,(1,2,3)¹³C—N-2-propene-1-yl-2-chloro-(R)-aminoindan,N-2-propene-1-yl-3-chloro-cis-(R)-aminoindan andN-2-propene-1-yl-3-chloro-trans-(R)-aminoindan; also referred to asN-(2-chloroallyl)-1-(R)-aminoindan,(1,2,3)¹³C—N-2-propene-1-yl-2-chloro-(R)-aminoindan,cis-N-(3-chloroallyl)-1(R)-aminoindan andtrans-N-(3-chloroallyl)-1-(R)-aminoindan (referred to hereinafter as2-chloro-AAI, (1,2,3)¹³C-2-chloro-AAI, cis-3-chloro-AAI andtrans-3-chloro-AAI, respectively).

It will be noted that the structure of the compounds of this inventionincludes an asymmetric carbon atom and thus the compounds occur asracemates, racemic mixtures, and isolated single enantiomers. All suchisomeric forms of these compounds are expressly included in thisinvention. Each stereogenic carbon may be of the R or S configuration.It is to be understood accordingly that the isomers arising from suchasymmetry (e.g., all enantiomers and diastereomers) are included withinthe scope of this invention, unless indicated otherwise. Such isomerscan be obtained in substantially pure form by classical separationtechniques and by stereochemically controlled synthesis, such as thosedescribed in “Enantiomers, Racemates and Resolutions” by J. Jacques, A.Collet and S. Wilen, Pub. John Wiley & Sons, NY, 1981. For example, theresolution may be carried out by preparative chromatography on a chiralcolumn.

It will also be noted that any notation of a carbon in structuresthroughout this application, when used without further notation, areintended to represent all isotopes of carbon, such as ¹²C or ¹³C.Furthermore, any compounds containing ¹³C may specifically have thestructure of any of the compounds disclosed herein.

A characteristic of a compound refers to any quality that a compoundexhibits, e.g., peaks or retention times, as determined by ¹H nuclearmagnetic spectroscopy, mass spectroscopy, infrared, ultraviolet orfluorescence spectrophotometry, gas chromatography, thin layerchromatography, high performance liquid chromatography, elementalanalysis, Ames test, dissolution, stability and any other quality thatcan be determined by an analytical method. Once the characteristics of acompound are known, the information can be used to, for example, screenor test for the presence of the compound in a sample.

As used herein, a “pharmaceutically acceptable” carrier or excipient isone that is suitable for use with humans and/or animals without undueadverse side effects (such as toxicity, irritation, and allergicresponse) commensurate with a reasonable benefit/risk ratio.

Specific examples of pharmaceutical acceptable carriers and excipientsthat may be used to formulate oral dosage forms are described, e.g., inU.S. Pat. No. 6,126,968 to Peskin et al., issued Oct. 3, 2000.Techniques and compositions for making dosage forms useful in thepresent invention are described-in the following references: 7 ModernPharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979);Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel,Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976);Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company,Easton, Pa., 1985); Advances in Pharmaceutical Sciences (DavidGanderton, Trevor Jones, Eds., 1992); Advances in PharmaceuticalSciences Vol 7. (David Ganderton, Trevor Jones, James McGinity, Eds.,1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugsand the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989);Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs andthe Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); DrugDelivery to the Gastrointestinal Tract (Ellis Horwood Books in theBiological Sciences. Series in Pharmaceutical Technology; J. G. Hardy,S. S. Davis, Clive G. Wilson, Eds.); Modern Pharmaceutics Drugs and thePharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T.Rhodes, Eds.).

Tablets may contain suitable binders, lubricants, disintegrating agents,coloring agents, flavoring agents, flow-inducing agents, and meltingagents. For instance, for oral administration in the dosage unit form ofa tablet or capsule, the active drug component can be combined with anoral, non-toxic, pharmaceutically acceptable, inert carrier such aslactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose,dicalcium phosphate, calcium sulfate, mannitol, sorbitol,microcrystalline cellulose and the like. Suitable binders includestarch, gelatin, natural sugars such as glucose or beta-lactose, cornstarch, natural and synthetic gums such as acacia, tragacanth, or sodiumalginate, povidone, carboxymethylcellulose, polyethylene glycol, waxes,and the like. Lubricants used in these dosage forms include sodiumoleate, sodium stearate, sodium benzoate, sodium acetate, sodiumchloride, stearic acid, sodium stearyl fumarate, talc and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, croscarmellose sodium, sodium starchglycolate and the like.

As used herein, “drug substance” refers to the active ingredient in adrug product, which provides pharmacological activity or other directeffect in the diagnosis, cure, mitigation, treatment, or prevention ofdisease, or to affect the structure or any function of the body of manor animals.

As used herein, “drug product” refers to the finished dosage formcontaining the drug substance as well as at least one pharmaceuticallyacceptable carrier.

As used herein, a composition that is “free” of a chemical entity meansthat the composition contains, if at all, an unavoidable level of thechemical entity but no more.

As used herein, “chloride-containing compound” refers to any compoundcontaining at least one chloride ion (e.g., HCl).

As used herein, “stability testing” refers to tests conducted atspecific time intervals and various environmental conditions (e.g.,temperature and humidity) to see if and to what extent a drug productdegrades over its designated shelf life time. The specific conditionsand time of the tests are such that they accelerate the conditions thedrug product is expected to encounter over its shelf life.

Propargylated aminoindan refers to a compound having an aminoindanmoiety with a propargyl substituent on the nitrogen atom, whether or notthere exist any other substituents.

Specific salts provided by this invention are the mesylate, maleate,fumarate, tartrate, hydrochloride, hydrobromide, esylate,p-toluenesulfonate, benzoate, acetate, phosphate and sulfate salts.

For the preparation of pharmaceutically acceptable acid addition saltsof the compounds of the invention, the free base can be reacted with thedesired acids in the presence of a suitable solvent by conventionalmethods. Similarly, an acid addition salt may be converted to the freebase form in a known manner.

U.S. Pat. No. 6,126,968, the entire contents of which are incorporatedherein by reference, disclosed that the stability of formulationscomprising PAI can be significantly improved by the incorporation ofrelatively large amounts of certain alcohols. In particular, the alcoholis selected from the group of pentahydric or hexahydric alcohols (U.S.Pat. No. 6,126,968). The alcohol is typically selected from mannitol,xylitol or sorbitol (U.S. Pat. No. 6,126,968). The composition mayfurther comprise citric acid (U.S. Pat. No. 6,126,968).

(R)-PAI itself may be prepared, for example, according to the processdescribed in Example 6B of WO 95/11016.

EXPERIMENTAL DETAILS

2-chloro-AAI, cis-3-chloro-AAI and trans-3-chloro-AAI can be detected byany of the following methods: UV, fluorescence, and mass spectroscopy.In a specific embodiment, the compounds were analyzed by at least twodifferent analytical methods: A GC-MS or HPLC where detection was byeither UV, MS or fluorescence.

Examples 1-4 provide the details of the synthesis of the hydrochloridesalt of the four chlorinated N-allyl-(R)-aminoindans. Example 5 providesdetails on the mesylate salts. Analogous methods are used to produce thehydrochloride salt of the corresponding (S) enantiomers as well as theracemic mixture. Other salts are produced by use of the desired acid inthe procedure or by neutralizing the HCl salt and treatment with thedesired acid and crystallizing the compound in the presence of suitablesolvents.

Example 1 Preparation of 2-chloro-(R)-AAI-HCl

-   1. (R)-PAI base (30 g) and 32% HCl (100 ml) were refluxed for 33    hours (see scheme 2). The reaction mixture was cooled, toluene    (150 ml) and water (150 ml) were added and the mixture was stirred    for 15 min. The aqueous phase was separated, brought to pH 14 with    47% NaOH and extracted with 150 ml toluene. The organic phase was    evaporated to give 36 g dark brown oil which exhibited 3 spots in    TLC, two of which were the desired compounds    (hexane-4/EA-6,2-Chloro-AAI base: R_(f)=0.67; cis-3-chloro-AAI base:    R_(f)=0.33, visualized in UV). The third spot had the same R_(f) as    the starting material (0.47) and it was thus thought to be the    starting material. However, when trans-3-chloro-AAI (see below) was    synthesized it was determined that both the trans and the starting    material have the same R_(f) values under the TLC conditions used.    Subsequent testing revealed that third spot was due mostly to PAI    and only trace amounts of the trans isomer were formed.-   2. The compounds formed in step 1 were separated by filtering-column    chromatography [Aldrichimica Acta, 21(4), 106-107 (1998)]. Thus 15 g    of the product of step 1 was separated on 400 g silica (Merck    type 9385) with a mixture of hexane-7/EA-3 to give 5.6 g pure    (R)-2-chloro-AAI (15% overall yield) and 5.0 g cis-3-chloro-AAI base    (13% overall yield for steps 1 and 2).-   3. To 6.7 g of 2-chloro-AAI base in 100 ml diethyl ether was added 9    ml of 14.5% HCl/ethanol solution. The reaction mixture was stirred    for ½ hr at ambient temperature and ½ hr at 5-10° C. The precipitate    was filtered, washed with ether and dried in vacuum at 50° C. to    give 7.1 g (90% yield) of the pure compound, m.p.=166-169° C. (see    scheme 2).

The compound exhibited satisfactory NMR and IR spectra which confirmedits structure.

¹H-NMR Spectrum

The ¹H-NMR spectrum is shown in FIG. 1. NMR Peak assignments are listedbelow:

Proton δ (ppm) Multiplicity Coupling Constant (J, Hz) H1 (1H) 4.80 dd 7,5 H2 (2H) 2.33 m — H3^(I) (1H) 2.82 ddd 17, 8, 6 H3^(II) (1H) 3.18 dt17, 8 H5, H6, H7 (3H) 7.24-7.25 m — H8 (1H) 7.85 d 15 H10 (2H) 3.83,3.96 AB q 15 H12^(I) (1H) 5.65 s — H12^(II) (1H) 5.95 s — H13 (2H)10.10  broad s —Mass Spectroscopy (MS)

The mass spectrum of 2-chloro-AAI-HCl was obtained using a Finnigan 4000Quadropole Low Resolution Mass Spectrometer, operated in electron impact(EI) mode. The electron impact (EI) spectrum exhibits molecular ions atm/z 207 [M]^(+•) and 206 [M^(+•-H]) ^(+•), and characteristic fragmentsat m/z 171 [M^(+•)-HCl]^(+•), 132 [M^(+•)-C3H4Cl^(•)]⁺ and 116[M^(+•)-C3H6ClN^(•)]⁺. The EI spectrum is in agreement with themolecular formula of 2-chloro-AAI.

Elemental Analysis

Elemental Analysis Calculated C: 59.03% H: 6.19% N: 5.74% Found C:58.93% H: 6.20% N: 5.68% These results correspond to the molecularformula.FT-IR Spectrum

The infrared (FT-IR) spectrum of 2-chloro-AAI-HCl is shown in FIG. 2.

Example 2 Preparation of (1,2,3)¹³C-2-chloro-AAI-HCl

A mixture of (1,2,3) ¹³C-aminoindan (420 mg, 3.08 mmol) and potassiumcarbonate (633 mg, 4.57 mmole) in 5 ml of acetonitrile was heated to60-65° C. and 2,3-dichloro-1-propene (422 μl, 4.57 mmole) was added inone portion. Heating at 60-65° C. was continued overnight after whichwas added 20 ml of water. The resulting mixture was extracted twice with20 ml of toluene, the combined extract dried over magnesium sulfate andthe solvents evaporated under reduced pressure. The product was purifiedby column chromatography on silica gel eluting with hexane:ethylacetate(2:1). The combined fractions were isolated, dissolved in ether andtreated with ethanolic HCl solution to give the title compound as awhite solid after cooling and washing with ether and drying in vacuo(495 mg, 65% yield). The NMR spectrum of this compound was identical tothe unlabelled compound of Example 1.

The (1,2,3)¹³C-aminoindan starting material for ¹³C-2-Cl-AAI wasprepared in seven steps starting with (1,2)-¹³C-phenyl acetic acid usingstandard chemistry reactions familiar to one skilled in the art. Thethird ¹³C-labelled carbon was introduced with K¹³CN as shown in thefollowing reaction scheme:

(1,2,3)¹³C-aminoindan was isolated in 51% overall yield and hadidentical chromatographic and spectrographic properties to an aminoindanreference standard, except that the mass spectrograph (ESI) had[M+H]+=137.

Elemental Analysis

Elemental Analysis Calculated C: 59.51% H: 6.12% N: 5.67% Cl: 28.70%Found C: 58.47% H: 6.12% N: 5.54% Cl: 28.80%

Mass Spectroscopy (m/e):

M+1=211

M−HCl=175

C₉H₉=120

Example 3 Preparation of trans-3-chloro-AAI-HCl

-   1. A 250 ml round bottom flask equipped with a mechanical stirrer    and nitrogen inlet was charged with (R)-AI (10 g, 75 mmol), K₂CO₃    (10.36 g, 75 mmol) and 26 ml N,N-dimethylacetamide. The reaction    mixture was heated to 60° C. and 1,3-dichloropropene (8.35 ml, 0.8    eq., Aldrich 40, 373-3, tech., 80%, mixture of isomers) in toluene    (9 ml) were added dropwise within 10 min. After another 4.5 hr of    stirring the reaction mixture was cooled and 60 ml water and 30 ml    toluene were added. The aqueous phase was separated and extracted    again with 30 ml toluene. The combined toluene extracts were washed    with 50 ml water, then 50 ml water were added and the pH was    adjusted to 2.5 with 6NH₂SO₄. The water phase was separated, 50 ml    toluene was added and the pH was adjusted to 6.5. The organic phase    was separated, the water phase was extracted with another portion of    toluene (30 ml), the toluene extracts were combined and evaporated    to give 12.2 g (78%) crude products. TLC (hexane-4/EA-6) showed 2    main products: trans-3-chloro-AAI, R_(F)=0.47; cis-3-chloro-AAI,    R_(F)=0.33 (see scheme 1).-   2. The separation of trans-3-chloro-AAI from the 12.2 g crude    cis/trans mixture was done by filtering-column chromatography over    400 g silica (Merck type 9385) with an eluent composed of EA/hexane    (3/7). The yield of pure trans-3-chloro-AAI was 4.5 g (29% overall    yield of steps 1 and 2).-   3. To 4.5 g of trans-3-chloro-AAI base (from step 2) in 80 ml    diethyl ether was added 14.5% HCl/ethanol solution. The reaction    mixture was stirred for ½ hr at ambient temperature and ½ hr at    5-10° C. The precipitate was filtered, washed with ether and dried    in vacuum at 50° C. to give 4.9 g (94% yield) of the pure compound,    m.p.=192-195° C. (see scheme 1). The compound exhibited satisfactory    NMR and MS spectra which confirmed its structure.

NMR Peak Assignments are Listed Below

Proton δ (ppm) Multiplicity H1 (1H) 4.75 dd H2a (1H) 2.24 m H2b (1H)2.40 m H3^(I) (1H) 2.86 ddd H3^(II) (1H) 3.18 dt H5, H6, H7 (3H)7.24-7.35 m H8 (1H) 7.81 d H10 (2H) 3.76, 3.78 m H11 (1H) 6.70 dt H12(1H) 6.30 dd H13 (2H) 10.10  broad s

Example 4 Preparation of cis-3-chloro-AAI-HCl

Steps 1 and 2 of Example 1 (see scheme 2) or Example 3 (see scheme 1)can be followed in preparation of cis-3-chloro-AAI. Then, to 5.0 g ofcis-3-chloro-AAI base in 90 ml diethyl ether was added 7 ml of 14.5%HCl/ethanol solution. The reaction mixture was stirred for ½ hr atambient temperature and ½ hr at 5-10° C. The precipitate was filtered,washed with ether and dried in vacuum at 50° C. to give 5.3 g (90%yield) of the pure compound, m.p.=164-166° C. The compound exhibitedsatisfactory NMR and MS spectra which confirmed its structure.

NMR Peak Assignments are Listed Below

Proton δ (ppm) Multiplicity H1 (1H) 4.75 dd H2a (1H) 2.24 m H2b (1H)2.40 m H3^(I) (1H) 2.86 ddd H3^(II) (1H) 3.18 dt H5, H6, H7 (3H)7.24-7.35 m H8 (1H) 7.81 d H10 (2H) 3.76, 3.78 AB q H11 (1H) 6.70 dt H12(1H) 6.30 dd H13 (2H) 10.10  broad s

Example 5 Preparation of the Mesylate Salts

The hydrochloride salts of the three chlorinated N-allyl aminoindansprepared in examples 1, 3, and 4 were neutralized, the bases separated,dissolved in ether (8 volumes) and cooled to 5° C. Methanesulfonic acidwas added and the reaction mixture was stirred for another hour,filtered, washed and dried to give the mesylate salts (88-96% yield, seescheme 3).

2-Chloro-AAI-MES was obtained in 96% yield, m.p.=120-123° C. andexhibited satisfactory NMR and MS spectra which confirmed its structure.

cis-3-Chloro-AAI-MES was obtained in 93% yield, m.p.=116-118° C. andexhibited satisfactory NMR and MS spectra which confirmed its structure.

trans-3-Chloro-AAI-MES was obtained in 88% yield, m.p.=77-80° C. andexhibited satisfactory NMR and MS spectra which confirmed its structure.

Example 6 Testing for Presence of Chlorinated N-allyl aminoindanBy-Products in the Manufacture of PAI-HCl

N-(2-chloroallyl)-1-(R)-aminoindan,cis-N-(3-chloroallyl)-1-(R)-aminoindan,trans-N-(3-chloroallyl)-1-(R)-aminoindan,N-(2-chloroallyl)-1-(S)-aminoindan,cis-N-(3-chloroallyl)-1-(S)-aminoindan andtrans-N-(3-chloroallyl)-1-(S)-aminoindan are useful as referencestandards to detect trace amounts of each of the compounds as apotential impurity in a drug product. Under specific conditions, forexample, 2-Chloro-AAI and cis-3-chloro-AAI can be formed from (R) —PAI.Similarly, the (S) enantiomers of the compounds can be formed from(S)-PAI. U.S. Pat. No. 5,532,415 (PCT Application Publication No. WO95/11016) and U.S. Pat. No. 6,277,886 (PCT Application Publication No.WO 98/02152) disclosed (R)-PAI and (S)-PAI, respectively, theirpreparation, and various pharmaceutically acceptable salts thereof.Detection methods include the following:

-   -   A) GC-MS Method: Using a suitable instrument (e.g., HP-5890        Series II) fitted with a fused silica capillary column with        helium carrier gas, samples are detected with a mass selective        HP-5971 (EI) detector in the single ion monitoring mode        monitoring peaks (for example) with m/z: 172, 206 and 208.        Temperatures and flow rates are adjusted to achieve system        suitability.    -   B) HPLC-UV Method: Using a suitable column (e.g., Lichrosphere        60 RP column) peaks are monitored with UV detection at 210 nm or        fluorescence excitation at 260 nm (emission at 290 nm).    -   C) LC/MS:MS Method: Using a suitable instrument (e.g., Agilent        1100 with an Applied Biosystem MDS Sciex API 4000 detector        equipped with a turbo ion spray interface) set to detect minute        quantities of the claimed compounds. In general, Multiple        Reaction Mode detection is used for the ions: 208/117, 211/120,        208/117, 172/117.

A sample of PAI-HCl was injected into an HPLC system equipped with twodifferent detection modes, with eluent A followed by injections ofmarkers and spiked samples, and the results are presented in Table 1:

TABLE 1 peaks rrt 1.58 rrt 1.86 rrt 1.97 rrt 2.13 Substance UV Fl. UVFl. UV Fl. UV Fl. PAI + + + − − − + + PAI + trans 3- + + + − ++ ++ + +PAI + cis 3-Cl + + + − − − ++ ++ PAI + 2-Cl ++ n.d. + n.d. − n.d. + n.d.PAI + + + ++ − − − + + indanone trans 3-Cl − − − − + + − − cis 3-Cl − −− − − − + + 2-Cl + n.d. − n.d. − n.d. − n.d. indanone − − + − − − − − −no response in the specified retention time n.d. not determined +response in the specified retention time ++ increased response due tospiking

According to these results, 2-chloro-AAI, cis 3-chloro-AAI and indanonewere present in the tested sample.

The same samples were subsequently injected into the HPLC system witheluent B and the following results were obtained (Table 2):

TABLE 2 peaks rrt 1.70 rrt 1.90 rrt 2.10 rrt 2.44 Substance UV Fl. UVFl. UV Fl. UV Fl. PAI + + − − + − + + PAI + trans 3- + + − − ++ ++ + +Cl PAI + cis 3-Cl + + − − + − ++ ++ PAI + 2-Cl ++ n.d. − n.d. + n.d. +n.d PAI + + + ++ − + − + + indanone trans 3-Cl − − − − + + − − cis 3-Cl− − − − − − + + 2-Cl + n.d. − n.d. − n.d. − n.d. indanone − − + − − − −− − response in the specified retention time ++ increased response dueto spiking − no response in the specified retention time n.d. notdetermined

These results show the presence of 2-chloro-AAI, cis-3-chloro-AAI and anunidentified peak. The presence of the trans-3-chloro-AAI can be ruledout since the response of the trans-3-chloro-AAI related peak wasachieved only by UV detection and not by fluorescence in spite of thepositive fluorimetric characteristics of the molecule.

A summary of the results obtained by the HPLC system is shown in Table3:

TABLE 3 Eluent A Eluent B Substance UV Fl. UV Fl. trans 3-Cl — — v — cis3-Cl v v v v 2-Cl v n.d. v n.d. indanone v x — x v present in thespecified analytical method — absent in the specified analytical methodx non fluorescent molecule n.d. not determined

A peak which does not appear in one of the systems in spite of themolecule's ability to absorb UV or emit fluorescence radiation negatesthe presence of its corresponding substance. Hence, it can be concludedthat the 2-chloro-AAI and the cis-3-chloro-AAI are the only chlorocontaining by-products in this sample.

Three additional samples of PAI-HCl were analyzed as described above.Only 2-chloro-AAI and cis-3-chloro-AAI were identified in these samples.However, in a fourth sample, traces of trans 3-chloro-AAI were alsoidentified.

Accordingly, the fourth sample and one of the earlier samples werefurther analyzed by GC-MS. The detection was performed using single ionmonitoring mode and the results obtained confirmed that the fourthsample contained all three chlorinated N-allyl aminoindans (2-Cl, cisand trans 3-Cl) while the previous sample contained only the first andsecond impurities.

Example 7 Analysis of Rasagiline Formulations

Rasagiline was formulated as a tablet in two different formulations andDW (double weight) as shown in Table 4 below.

TABLE 4 Strength 0.5 mg 1.0 mg Formulation Code DW Ingredient Quantityper Tablet [mg] Rasagiline Mesylate 0.78* 1.56** 1.56** PregelatinizedStarch 10.0 10.0 20.0 Talc 2.0 2.0 4.0 Mannitol 79.62 78.84 159.24Starch 10.0 10.0 20.0 Colloidal Anhydrous 0.6 0.6 1.2 Silica StearicAcid 2.0 2.0 4.0 Total Weight per Tablet 105.0 105.0 210.0 [mg] *0.78 mgrasagiline mesylate is equivalent to 0.5 mg rasagiline base **1.56 mgrasagiline mesylate is equivalent to 1.0 mg rasagiline base

Drug product formulations were analyzed for 2-Chloro-AAI after storageunder various conditions. Representative results for formulations usingthe sensitive LC/MS/MS method are summarized in Table 5.

TABLE 5 Representative results of 2-Chloro-AAI measured in formulatedRasagiline Drug Product packaged in HDPE containers or blisterpacks Dose2-ClAAI (mg) Container Storage conditions (ppm) 1 Blister-ALU- 6 M 40°C. 75RH 10.2 ALU 0.5 Blister-ALU- 6 M 40° C. 75RH 9.3 ALU 1 Blister-ALU-6 M + 5 M 40° C. 75RH 8.4 ALU 0.5 Blister-ALU- 6 M 40° C. 75RH 5.3 ALU 2Blister-ALU- 6 M 40° C. 75RH 4.3 ALU 1 Blister-ALU- 5 M 40° C. 75RH 3.5ALU 2 Blister-ALU- 6 M + 5 M 40° C. 75RH 2.8 ALU 2 Blister-ALU- 5 M 40°C. 75RH 2.4 ALU 0.5 Blister-ALU- 29 M 25° C. 60RH 1.1 ALU 1 60 cc 4 M40° C. 75RH <1 ppm 0.5 Blister-ALU- 29 M 25° C. 60RH <1 ppm ALU 0.5Blister-ALU- 29 M 25° C. 60RH <1 ppm ALU 1 Blister-ALU- 11 M 30° C. 60RH<1 ppm ALU 0.5 30 cc 39 M 25° C. 60RH <1 ppm 1 60 cc 6 M 40° C. 75RH <1ppm 1 60 cc 6 M 40° C. 75RH <1 ppm 1 60 cc 6 M + 5 M 40° C. 75RH <1 ppm1 30 cc 6 M + 5 M 40° C. 75RH <1 ppm 0.5 30 cc 39 M 25° C. 60RH <QL 0.530 cc 39 M 25° C. 60RH <QL 1 DW 30 cc 39 M 25° C. 60RH <QL 1 DW 30 cc 39M 25° C. 60RH <QL 1 DW 30 cc 39 M 25° C. 60RH <QL 1 DW 30 cc 39 M 25° C.60RH <QL 0.5 30 cc 40 M 25° C. 60RH <QL 0.5 30 cc 40 M 25° C. 60RH <QL 160 cc 6 M 40° C. 75RH <QL 1 DW 60 cc 5 M 40° C. 75RH <QL 1 DW 60 cc 5 M40° C. 75RH <QL 1 DW 60 cc 5 M 40° C. 75RH <QL 0.5 30 cc 39 M 25° C.60RH <QL 0.5 30 cc 39 M 25° C. 60RH <QL 0.5 30 cc 39 M 25° C. 60RH <QL 1DW 30 cc 39 M 25° C. 60RH <QL 1 DW 30 cc 39 M 25° C. 60RH <QL 0.5 30 cc40 M 25° C. 60RH <QL 0.5 30 cc 40 M 25° C. 60RH <QL 1 DW 60 cc 4 M 40°C. 75RH <QL 2 30 cc 6 M 40° C. 75RH <QL 1 DW 60 cc 5 M 40° C. 75RH <QL 1DW 60 cc 5 M 40° C. 75RH <QL 1 DW 60 cc 5 M 40° C. 75RH <QL 1 DW 60 cc 5M 40° C. 75RH <QL 1 60 cc 6 M + 5 M 40° C. 75RH <QL 1 60 cc 6 M + 5 M40° C. 75RH <QL 2 30 cc 6 M + 5 M 40° C. 75RH <QL 0.5 30 cc 40 M 25° C.60RH <DL 0.5 30 cc 40 M 25° C. 60RH <DL 1 DW Blister-ALU- 18 M 25° C.60RH <DL ALU 1 DW 30 cc 28 M 25° C. 60RH <DL 1 DW 30 cc 28 M 25° C. 60RH<DL 0.5 Blister-ALU- 6 M 30° C. 60RH <DL ALU 2 Blister-ALU- 11 M 30° C.60RH <DL ALU 1 DW 60 cc 4 M 40° C. 75RH <DL 1 DW 60 cc 4 M 40° C. 75RH<DL 1 DW 60 cc 4 M 40° C. 75RH <DL 2 30 cc 6 M 40° C. 75RH <DL 1 DW 60cc 5 M 40° C. 75RH <DL 2 60 cc 6 M + 5 M 40° C. 75RH <DL 2 60 cc 6 M + 5M 40° C. 75RH <DL 1 Blister-ALU- 11 M 25° C. 60RH <DL ALU 1 Blister-ALU-5 M 30° C. 60RH <DL ALU 2 Blister-ALU- 5 M 30° C. 60RH <DL ALU 1 DW 60cc 4 M 40° C. 75RH <DL 2 60 cc 6 M + 5 M 40° C. 75RH <DL 1 DW 30 cc 5 M25° C. 60RH <DL 1 DW 30 cc 5 M 25° C. 60RH <DL 1 DW 30 cc 5 M 25° C.60RH <DL 1 DW Blister-ALU- 5 M 25° C. 60RH <DL ALU 1 DW Blister-ALU- 5 M25° C. 60RH <DL ALU 1 DW 30 cc 5 M 25° C. 60RH <DL 1 DW Blister-ALU- 5 M25° C. 60RH <DL ALU 1 DW 30 cc 3 M 25° C. 60RH <DL 1 DW 30 cc 3 M 25° C.60RH <DL 1 Blister-ALU- 5 M 25° C. 60RH <DL ALU (DW indicates a doubleweight formulation. RH is relative humidity.) (The 2 mg dose isformulated like the other dose forms, except with more active.)Observations

2-Chloro-AAI was not observed as an impurity in the drug substance. Insome cases after 6 months storage at 40° C. and 75% relative humidity ina blister pack, 2-Chloro-AAI was observed at levels as high as 8-10 ppm.

Discussion

It has been observed that under certain conditions (e.g. 80° C.-100° C.,presence of a chloride ion source and low pH), the triple bond ofrasagiline in rasagiline mesylate is susceptible to chlorination to formtwo of the possible chlorinated allyl aminoindans (Cl-AAI'S):N-2-propene-1-yl-2-chloro-(R)-aminoindan andN-2-propene-1-yl-3-chloro-cis-(R)-aminoindan.N-2-propene-1-yl-3-chloro-trans-(R)-aminoindan was not formed inrasagiline mesylate drug product under any of the tested conditions.However, trace amounts of the trans isomer were detected in one batch of(R)-PAI-HCl as noted above. This high degree of stereospecificity wasconfirmed by independent synthesis of trans-3-chloro-AAI.

Miniscule amounts of 2-Cl-AAI may potentially be generated during themanufacture of rasagiline if any of the reagents contain chloride. Thus,unless the proper precautions are exercised rasagiline may becontaminated with these two chlorinated impurities. Similarly, theformulation excipients must be chosen with low chloride content in orderto limit potential sources of chloride ions to avoid the production of2-Cl-AAI.

The other chlorinated degradant (cis-3-Cl-AAI) is formed more readilythan 2-Cl-AAI and under certain conditions it is also useful to monitorthe presence of cis-3-Cl-AAI in order to alert one to the presence of2-Cl-AAI.

In order to minimize the formation of 2-Cl-AAI in the rasagilinemesylate drug product, potential sources of chloride ions during thedrug substance synthesis were further limited by replacing thepropargylation agent propargyl chloride with propargylbenzene sulfonate,and by limiting the chloride ion content in methanesulfonic acid, whichis used in the last reaction step, to not more than 500 ppm.

In addition, during the formulation development of the drug product, aspecial effort was made to select excipients with low chloride contentin order to limit potential sources of chloride ions. The content of2-Cl-AAI was determined in the drug product at release and during thestability studies (limited to not more than 0.0030%, i.e. 30 ppm) usingGC/MS.In view of the fact that 2-Cl-AAI is a potential degradationproduct of rasagiline as described above, a sensitive screening methodis needed to monitor the levels of 2-Cl-AAI in the production ofrasagiline. In order to address this need, the subject inventionprovides a sensitive gas chromatography method to monitor the levels ofthe 2-Cl-AAI in the rasagiline drug substance and drug product.Detection is conducted by mass spectroscopy under SIM conditions whichprovides high selectivity of the GC/MS method, Screening may also beaccomplished using high performance liquid chromatography (HPLC)equipped with a UV/fluorescence detector or a MS:MS detector.

1. A process for producing validated batch of a pharmaceutical productcontaining N-propargyl-1(R)-aminoindan mesylate and at least onepharmaceutically acceptable carrier for distribution comprising a)producing a batch of the pharmaceutical product; b) performing stabilitytesting with a sample of the batch; c) determining the total amount ofN-2-propene-1-yl-2-chloro-(R)-aminoindan and any salts thereof in thesample of the batch after stability testing; and d) validating the batchfor distribution only if the sample of the batch after stability testingcontains less than 30 ppm in total ofN-2-propene-1-yl-2-chloro-(R)-aminoindan and salts thereof.
 2. Theprocess of claim 1, wherein the batch is validated if the sample of thebatch after stability testing contains a total amount greater than 0.7ppm of N-2-propene-1-yl-2-chloro-(R)-aminoindan and salts thereof, asdetermined by a LC/MS:MS Method.
 3. The process of claim 2, wherein thebatch is validated if the sample of the batch after stability testingcontains a total amount greater than 2 ppm ofN-2-propene-1-yl-2-chloro-(R)-aminoindan and salts thereof, asdetermined by a LC/MS:MS Method.
 4. The process of claim 3, wherein thebatch is validated if the sample of the batch after stability testingcontains a total amount greater than 4 ppm ofN-2-propene-1-yl-2-chloro-(R)-aminoindan and salts thereof, asdetermined by a LC/MS:MS Method.
 5. The process of claim 1, wherein thebatch is validated only if the sample of the batch after stabilitytesting contains a total amount less than 4 ppm ofN-2-propene-1-yl-2-chloro-(R)-aminoindan and salts thereof, asdetermined by a LC/MS:MS Method.
 6. The process of claim 5, wherein thebatch is validated only if the sample of the batch after stabilitytesting contains a total amount less than 2 ppm ofN-2-propene-1-yl-2-chloro-(R)-aminoindan and salts thereof, asdetermined by a LC/MS:MS Method.
 7. The process of claim 6, wherein thebatch is validated only if the sample of the batch after stabilitytesting contains a total amount less than 0.7 ppm ofN-2-propene-1-yl-2-chloro-(R)-aminoindan and salts thereof, asdetermined by a LC/MS:MS Method.
 8. The process of claim 1, wherein instep c), the amount is determined using a measurement of mass,ultraviolet absorption, refractive index, ionization or voltammogram. 9.A process for producing a pharmaceutical product containingN-propargyl-1(R)-aminoindan mesylate and at least one pharmaceuticallyacceptable carrier, which pharmaceutical product does not contain anundesirable chlorinated N-allyl aminoindan comprising a) producing abatch of the pharmaceutical product; b) analyzing a sample of the batchto detect whether the sample contains a compound having the structure:

wherein one of R₁, R₂ or R₃ is Cl and the remainder are H, or a saltthereof, using a LC/MS:MS Method; and c) producing the pharmaceuticalproduct from the batch only if the sample does not contain theundesirable chlorinated N-allyl aminoindan.
 10. The process of claim 9,wherein the compound has the structure:


11. The process of claim 9, wherein the compound has the structure:


12. The process of claim 9, wherein the compound has the structure:


13. The process of claim 9, wherein the compound has the structure:


14. The process of claim 9, wherein the compound has the structure:


15. The process of claim 9, wherein the compound has the structure:


16. The process of claim 9, wherein the compound has the structure:


17. The process of claim 9, wherein the compound has the structure:


18. The process of claim 9, wherein the compound has the structure:


19. The process of claim 9, wherein the compound has the structure:


20. The process of claim 9, wherein the compound has the structure: